Anaesthetic steroids

ABSTRACT

AS AN ANEASTHETIC COMPOSITION FOR ANESTHETISING A SUBJECT BY PARENTERAL ADMINISTRATION, AN AQUEOUS SOLUTION OR SUSPENSION OF 3A-HYDROXY-5A-PREGNANE-11,20-DIONE AS PRINCIPAL ACTIVE INGREDIENT. IF THE COMPOSITION IS IN SOLUTION FORM IT WILL CONTAIN AT LEAST 1 MG./ML. OF THIS STEROID AND AT LEAST 1% BY WEIGHT (10 MG./ML.) OF A PARENTERALLY ACCEPTABLE NON-IONIC SURFACE ACTIVE AGENT HAVING AN HLB VALUE OF FROM 9-18 THE SOLUTION ALSO PREFERABLY CONTAINS TO INCREASE THE SOLUBILITY OF THE 3A-HYDROXY - 5A - PREGNANE - 11,20-DIONE, AT LEAST ONE STEROID OF THE FORMULA   3-HO,21-(R-O-)PREGNANE-11,20-DIONE   WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF A LOWER ALKANOYL GROUP, A HEMISUCCINOYL GROUP AND A BENZOYL GROUP. IF THE COMPOSITION IS IN SUSPENSION FORM IT WILL CONTAIN 0.1-2.0% BY WEIGHT OF THE PRINCIPAL ACTIVE STEROID, FROM 0.5-5.0% BY WEIGHT OF A NON-IONIC SURFACE ACTIVE AGENT HAVING AN HLB VALUE OF AT LEAST 9, AND, DESIRABLY, FROM 0.1-10% BY WEIGHT OF A SUSPENDING AGENT. THE COMPOSITION MAY BE PRESENTED IN DOSAGE UNIT FORM IN A CONTAINER CONTAINING 10 MG.-300 MG. OF THE PRINCIPAL ACTIVE STEROID.

United States Patent 3,816,624 ANAESTHETIC STEROIDS Benjamin Davis, Chalfont St. Peter, and Gordon Hanley Phillipps, Greenford, England, assignors to Glaxo Laboratories Limited, Middlesex, England No Drawing. Continuation-impart of application Ser. No. 47,163, June 17, 1970, now Patent No. 3,714,352, dated Jan. 30, 1973. This application Dec. 16, 1971, Ser. No. 208,922 The portion of the term of the patent subsequent to Jan. 30, 1990, has been disclaimed Int. Cl. A61k 17/00 US. Cl. 424-243 32 Claims ABSTRACT OF THE DISCLOSURE wherein R is selected from the group consisting of a lower alkanoyl group, a hemisuccinoyl group and a benzoyl group. If the composition is in suspension form it will contain 01-20% by weight of the principal active steroid, from 05-50% by weight of a non-ionic surface active agent having an HLB value of at least 9, and, desirably, from 01-10% by weight of a suspending agent. The composition may be presented in dosage unit form in a container containing mg.300 mg. of the principal active steroid.

This application is a continuation-in-part of application Ser. No. 47,163 filed on June 17, 1970 and now Pat. No. 3,714,352.

This invention is concerned with improvements in or relating to pharmaceutical preparations which may be in dosage unit form, having anaesthetic activity, more particularly aqueous preparations suitable for intravenous injection, and to a method of anaesthetising a subject using such a preparation.

It has long been known that a number of steroids give rise to profound depression of the central nervous system and act pharmacodynamically as anaesthetics or hypnotics. Such compounds have been the subject of considerable study in an attempt to find anaesthetics to replace such substances as thiopental sodium normally used but well known to be accompanied by some degree of hazard or disadvantage. The literature shows that very many steroid compounds have been studied in this regard. Reviews and discussions of some of the work carried out are to be found, for example, in Methods in Hormone Research (edited by Ralph I. Dorfman, vol. III, part A, Academic Press, London and New York 1964, pages 415- 475); H. Witzel, Z Vitamin Hormon-Fermentforsch 1959', 10, 46-74; H. Selye, Endocrinology, 1942, 30, 437-453; S. K. Figdor et al., J. Pharmacol. Exptl. Therap., 1957, 119 299-309 and Atkinson et al., J. Med. Chem. 1965, 8, 426-432.

It is stated in the Atkinson et al. paper that 3a-hydroxy- 5a-pregnane-ll,20-dione and its succinate have approximately the same hypnotic activity as each other and their 5,3-epimers. The SB-epimer, named Predione, is described in French Pat. No. 6555M, dated Dec. 23, 1968, as an anaesthetic for intravenous injection in the form of an aqueous solution wherein it is solubilized by agents including Tween and Emulphor. This 5,8-epimer is reported by Kappas et al., A.-M.A. Arch. Intern, Med., 105, pages 701-708 (1960) as causing pyrexia in man by both the intramuscular and intravenous routes.

A thorough review of the literature indicates that anaestheic steroids generally possess poor activity and/or long induction periods. With such compounds a variety of undesired side effects such as paraesthesia and thrombophlebitis and vein damage have been noted. Many steroid compounds having anaesthetic action are also of poor solubility and thus much research has hitherto been directed to the introduction of solubilising groups into such steroids, e.g. by the formation of partial esters with dior polybasic acids; such work has hitherto not resulted in the discovery of a satisfactory anaesthetic steroid compound. Anaesthetic steroids are generally relatively simple pregnane derivatives, often hydroxylated in the 3-position, the general trend having been in the latter case to study 3B-hydroxy compounds in preference to 3a-hydroxy compounds.

As a result of prolonged study of numerous steroids exhibiting anaesthetic activity we have found that 3ahydroxy 5a pregnane 11,20-dione (hereinafter called steroid I) has quite remarkable properties as an anaesthetic. This substance has but poor solubility in water and although referred to in the above cited literature as having hypnotic properties, has apparently been rejected by reason of its poor solubility and the difliculty to be anticipated in its use by intraveneous administration arising therefrom.

We have found however that steroid I can be brought into aqueous solution with the aid of certain non-ionic surface active agents to yield solutions of a sufiicient concentration for injection, the resulting solutions when injected showing excellent anaesthetic properties. We have also found that, unexpectedly, aqueous suspensions containing, as active ingredient, the said steroid I can be prepared in injectible form and have the same excellent anaesthetic properties. Although in such suspensions the steroid anaesthetic is in solid form, it appears that upon intravenous injection the steroid passes rapidly into solution in the blood.

Thus the aqueous solutions or suspensions of steroid I according to the invention induce anaesthesia and possess short induction periods, the anaesthetic action at suitable doses being indeed instantaneous; the solutions or suspen sions are thus excellent anaesthetics for inducing anaesthesia which is to be maintained e.g., by an inhalation an aesthetic such as ether, halothane, nitrous oxide, trichloroethylene etc. The solutions or suspensions are however capable of maintaining anaesthesia and analgesia to a sufiicient degree to enable various surgical operations to be conducted without the aid of an inhalation anaesthetic, the required degree of anaesthesia being maintained if necessary by repeated administration (or even continuous administration). Recovery from anaesthesia (where this is induced only by the solutions or suspensions of this invention) is excellent, the patient exhibiting a feeling of well-being in distinction to the unpleasant after eifects generally associated with conventional anaesthetics. Moreover, anaesthetic solutions or suspensions in accordance with the invention in general give rise to none of the undesired side-eifects hitherto associated with steroidal anaesthetics.

According to one aspect of the invention therefore, there are provided pharmaceutical compositions suitable for use by parenteral administration, comprising an aqueous solution of at least 1 mg./ml. of 3a-hydroxy-5a-pregnane-11,20-dione and at least 1% by weight (10 mg./ml.) of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9 but preferably less than 18.

The non-ionic surface active agents used for the purpose of this invention are generally those of the water-soluble type, preferably having an HLB value of at least about 12, advantageously at least about 13. Preferably the HLB value of the surface active agent is not greater than about 15. The surface active agent must naturally be one which is physiologically compatible, i.e. of itself give rise to no physiologically unacceptable side effects in the dosages employed in the intended species to be treated (man or animal).

As is well known to those skilled in the art, in the case of mixtures of surface active agents, the resultant HLB value of the mixture is determinative of the hydrophilic/ lipophilic balance (HLB) of the combination. Accordingly the expression HLB value as used herein, as is conventional, means in the case of mixtures of surface active agents, the resultant HLB value of such mixtures.

Surface active agents for use in accordance with the invention are for example to be found among the following non-ionic surfactants and classes of surfactants: Polyoxyethylated derivatives of fatty (C -C glyceride oils, e.g. castor oil, containing at least 35, e.g. from 35-45, or even 60 or more, oxyethylene groups, per mole of fatty oil. Polyoxyethylene ethers (containing from 10 to 30 oxyethylene groups) of long chain alcohols (containing for example from 12-18 carbon atoms).

Polyoxyethylene polyoxypropylene ethers containing from 5-160, for example from 15 to 35 and from 15 to 30 oxyethylene and oxypropylene groups respectively. Polyoxyethylene ethers (containing from 6 to 12 oxyethylene groups) of alkyl phenols the alkyl groups of which preferably contain 6-10 carbon atoms.

Polyoxyethylated (containing from 15 to 30 oxyethylene groups) fatty acid (e.g. C esters of sugar alcohol anhydrides e.g. sorbitan or mannitan. Long-chain (e.g. C alkanoyl monoand di-alkanolamides (the alkanol portions of which for example contain 1-5 C atoms) for example lauroyl monoand di-ethanolamides. Polyethylene glycol esters (containing from 6 to 40 ethylene oxide units) of long chain fatty acids (containing for example 12-18 C atoms) e.g. polyethylene glycol monooleate (containing for example 8 ethylene oxide units).

Examples of non-ionic surface active agents, of the foregoing types, useful in accordance with the invention include:

Cremophor EL, a polyoxyethylated castor oil containing about 40 ethyleneoxide units per triglyceride unit;

Tween 80, polyoxyethylene sorbitan monooleate containing about 20 ethylene Oxide units;

Tween 60, polyoxyethylene sorbitan monostearate containing about 20 ethylene oxide units; and

Tween 40, polyoxyethylene sorbitan monopalmitate containing about 20 ethyleneoxide units.

The expression solutions is used herein to denote liquids which have the appearence of true solutions and are thus optically clear and capable of passage, for example, through a micro-porous filter, irrespective of whether such solutions are true solutions in the classical chemical sense and irrespective of whether they are stable or metastable. Thus it may be that the steroid is associated with micelles. The solutions of this invention, irrespective of their precise physical nature, behave as true solutions for the practical purpose of intravenous injection.

It has been further found that the total amount of anaesthetic steroid which may be dissolved in accordance with the invention may be substantially increased by the presence of a steroid of general formula HO-- I wherein R is an alkanoyl group having a straight or branched chain (containing for example 2-4 carbon atoms which may, if desired be substituted, for example by a carboxyl groups) or an unsubstituted or substituted aroyl or aralkanoyl group. Such steroids of formula II thus act as solubility promoters for the steroid I and are capable of substantially increasing the amount of the latter which may be dissolved in the compositions of this invention. Moreover steroids of formula II, preferred members of which are those in which R is an acetyl, pro pionyl, iso-butyryl, hemisuccinoyl or benzoyl group, themselves possess anaesthetic activity although of a generally lower order than steroid I. Solutions containing steroid I together with a steroid of formula II may thus be prepared having a substantially greater anaesthetic potency than a solution of steroid I alone, due to the increased amount of steroid I which can be dissolved and the anaesthetic action of the steroid of formula 11 per se.

The proportion of surface active agent to be used in the solutions of this invention depends upon its nature and upon the concentration of steroid desired in the final composition.

In preferred solutions according to the invention the proportion of surfactant is preferably at least 5% by weight (50 mg./ml.) and advantageously above 10% by weight mg./ml.). -A very convenient proportion of surfactant has been found to be 20% by weight (200 mg./ml.) but 30% (3'00 mg./ml.) and up to 50% (500 mg./ml.) may be used. The proportions of surfactant are expressed by weight in relation to the total volume of the composition in metric units.

The solutions according to this invention may contain up to 40 or even 50% by weight of the total steroid of a compound of formula I I; as little as 5% of the total steroid present of a compound of formula II provides useful solubility promotion. For practical purposes it is preferred that of the total steroid at least 10% by Weight, and preferably not more than 30% by weight of the total steroid consists of a compound of formula II. Very satisfactory results have been achieved with a mixture of steroid I with a steroid of formula II in which the proportion of the steroid of formula H is about 25%.

As will be clear, the proportion of steroid I in the aqueous solution according to the invention depends upon the nature and amount of surface active agent used. and also upon the amount of steroid of formula II present (if used). The composition will contain at least 1 mgjml. of steroid I and solutions can be made containing for example 2 and 4 mg./ml.; using a steroid of formula I I as solubiliser the amounts of total steroid can be increased up to 50 mg./ml. although less than 30 mg./ml. total steroid and generally less than 20 mg./ml. will usually be satisfactory. A composition comprising 9 mg./ml. of steroid I to 3 mg./ml. of a compound of formula II in which R is acetyl has been found to be very satisfactory.

In all cases, as stated above the relative proportion of the various components are adjusted to give a clear solution.

In a preferred method of preparing the solutions according to the invention the steroid is first dissolved in the selected surfactant for example, with heating and the resulting solution dissolved in water. In this way in general it is possible to dissolve increased amounts of steroid I as compared with other methods.

However, the solution may also be prepared by shaking the steroid with an aqueous solution of the surface active agent. Alternatively the steroid may be dissolved in a volatile organic solvent advantageously having a boiling point of less than about 80 C. which is miscible with the surface active agent such as a volatile lower aliphatic ketone e.g. acetone or methyl ethyl ketone or a volatile halogenated hydrocarbon e.g. chloroform or methylene chloride. Acetone is particularly preferred for this purpose. The surface active agent is then added to this solution, the organic solvent removed by evaporation, for example by passing a stream of an inert gas through the solution e.g. nitrogen and the resulting solution of steroid in surfactant is mixed with Water. Simple tests enable one to determine the relative proportions of surface active agent required.

The anaesthetic solutions according to the invention are generally administered by intravenous injection although as is known in the anaesthetic art in certain cases, e.g. with young chlidren intramuscular injection might be preferred.

According to another aspect of the invention, a composition is prepared in the form of sterile aqueous suspensions for injection containing, as active ingredient, the said anaesthetic steroid I. p

The suspension according to the invention are prepared in generally conventional manner. Thus the suspensions will generally contain a parenterally acceptable surface active agent to assist dispersion of the active steroid and to prevent agglomeration of the particles.

Non-ionic surface active agents are generally suitable for this purpose. The suspensions in accordance with the invention preferably contain one or more non-ionic surfactants, the HLB value being preferably at least 9 but preferably below 15.

Where more than one surfactant is present the HLB value of an individual surfactant is preferably not greater than 30.

Particularly useful surfactants are those carrying a polyoxyethylene grouping chosen, for example from the following classes: Polyoxyethylated derivatives of fatty (C -C glyceride oils, e.g. castor oil, preferably containing from at least 35 (e.g. from 35 to 45 or 60 or more) oxyethylene groups, per mole of fatty oil. Polyoxyethylene ethers (containing from 10 to 30 oxyethylene groups) of long chain alcohols (containing for example from 12-18 carbon atoms, e.g. dodecanol).

Polyoxyethylene-polyoxypropylene ethers preferably containing from 5-160 (e.g. 15 to 150) and from 15 to 50 oxyethylene and oxypropylene groups respectively. Polyoxyethylene ethers (containing from 6 to 12 oxyethylene groups) of alkyl phenols the alkyl groups of which preferably contain 6-10 carbon atoms.

Polyoxyethylated (preferably containing from 15 to oxyethylene groups) fatty acid (e.g. (3 esters of sugar alcohol anhydrides e.g. sorbitan or mannitan.

Polyethylene glycol esters (preferably containing from 6 to 40 ethylene oxide units) of long chain fatty acids (containing for example 12-18 C atoms) e.g. polyethyleneglycol mono-oleate (preferably containing for example 8 ethylene oxide units).

Long-chain (e.g. C alkanoyl monoand di-alkanolamides (the alkanol portions of which for example contain 1-5 C atoms) for example lauroyl monoand diethanolamides are also useful.

Other useful surfactants include phosporlipids such as lecithins e.g. egg or soyabean lecithins.

Examples of non-ionic surface active agents, of the foregoing types, particularly useful in accordance with the invention include:

Cremophor EL, a polyoxyethylated castor oil containing about 40 ethylene oxide units per triglyceride unit;

Tween 80, polyoxyethylene sorbitan mono-oleate containing about 20 ethylene oxide units;

Tween 60, polyoxyethylene sorbitan monostearate containing about 20 ethylene oxide units;

Tween 40, polyoxyethylene sorbitan monopalmitate containing about 20 ethylene oxide units;

Pluronic F68, a block copolymer of ethylene oxide and propylene oxide containing about ethylene oxide units and about 40 propylene oxide units; and

Brij 35, polyoxyethylene dodecyl ether containing about 23 ethylene oxide units.

The suspensions according to the invention further desirably contain a parenterally acceptable suspending agent to assist in maintaining the steroid in suspension. Suspending agents which may be used include parenterally acceptable hydrophilic colloids such as dextran, preferably a dextran having an average molecular weight of from 15,000 to 70,000.

Various other types of suspending agents useful in the preparation of injectable pharmaceutical compositions are well known and may be used in the compositions in this invention, for example, polyvinylpyrrolidone, polyvinyl alcohol, sorbitol, mannitol, a polyoxyethylene glycol, carboxymethylcellulose, colloidal silica and colloidal silicates.

The suspensions according to the invention may if desired contain an antifoam agent, for example, a parenterally acceptable silicone antifoam agent, e.g. dimethyl polysilioxane.

The suspension may further include one or more parenterally acceptable, water-soluble substances serving to render the compositions approximately isotonic with blood, suitable substances for this purpose being dextrose or glycerol.

The anaesthetic steroid active ingredient in the suspension in accordance with this invention is preferably of very fine particle size, particle sizes below 5 nn. (average particle size) being preferred. Advantageously the average particle size of the steroid should be below 2 ,urn. The suspensions preferably contain 0.1 to 2.0% by weight of active steroid (steroid I).

It is particularly convenient to prepare the aforesaid steroid anaesthetic substance I in small particle form by rapid precipitation from solution in a suitable solvent. Thus for example the steroid may be dissolved in a solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran and the solution added to water preferably containing a surface active agent (for example of the aforementioned types) with agitation, for example with a high speed stirrer. The precipitation is preferably eifected at low temperature to promote formation of fine particles, e.g. at 5 C. Other methods of producing small size crystal material from solution are well known to those skilled in the art.

In general the suspensions according to the invention will contain at least 0.5% and preferably from 05-50% (by weight) of surface active agent. The proportion of suspending agent, when used, may be from 0.1-10% by Weight.

Where an antifoam substance is included this will generally be present in quite small proportions, for example of the order of from 50 to 150 ppm. by weight.

Compositions in accordance with the invention may take the form of a two-pack composition comprising a first container containing the principal active steroid (steroid I) and a second container containing the liquid injection vehicle, the contents of the two containers being intended for admixture by an anaesthetist, for example just prior to use.

The herein described compositions may be presented in the form of powders, e.g. wettable powders adapted to be readily dispersed in sterile water for injection, for example just prior to administration. Such wettable powders may be prepared using the same ingredients as in the preparation of suspensions, the various components being selecte in conventional manner, to provide a readily dispersable product. Preferably, the wetta'ble powders comprises a freeze-dried mixture of the active steroid and the surfactant. Such wettable powders are useful, for example, in the production of two-pack compositions of the type referred to above.

As is usual in the case of anaesthetics, the quantity of steroid I used to induce anaesthesia, whether presented as a solution or suspension, depends upon the weight of the individual to be anaesthetised. For intraveneous administration in the average man a dose of from 0.45 to 3.5 mg./kg. will in general be found to be satisfactory to induce anaesthesia, the preferred dose being within the range of from 0.7 to 2.5 mg./kg. Generally a dose of about 1.35 mg./'kg. is very satisfactory. The dose will naturally vary to some extent dependent upon the physical condition of the patient, and the degree and period of anaesthesia required, all as is well known in the art. It is thus possible by adjustment of the dose to achieve durations of anaesthesia varying from about minutes to up to an hour or more. If it is desired to maintain prolonged anaesthesia, repeated doses of the solutions or suspensions of this invention may be used, such repeated doses being generally either of the same order or lower than the original dose. Alternatively continuous administration may be undertaken at for example a rate of 0.09- 1.8 mg./kg./min.

Where the anaesthetic solutions or suspensions are administered intramuscularly, naturally higher doses are generally necessary.

The solutions or suspensions according to the invention are preferably presented in dosage unit form, i.e. in containers, for example ampoules or vials, each such container containing from 10 mg. to 300' mg. of the aforesaid steroid I. While, as stated above, the dose to be given to any particular patient will depend on his weight and physical condition and the degree and period of anaesthesia required, dosage units having a content of active ingredient within the range just mentioned will be found to provide the anaesthetist with a convenient quantity of anaesthetic in a single unit from which the particular dose required for a given patient may readily be taken. In each dosage unit, steroid I will be suspended or dissolved in a sterile, pyrogen-free parenterally acceptable liquid vehicle which may be one of the solutions or suspensions described earlier.

3a-Hydroxy-5a-pregnane-l1,20-dione (steroid I) can be prepared in any convenient manner for example as described by Camerino et al., Helv. Chim. Acta., 1953, 36, 1945 or by Nagata et al., Helv. Chim. Acta 1959, 42, 1399. In applying the last-mentioned process there have been encountered various difiiculties at several stages due to side reactions, which have been found to be due to epimerisation at position-17. As a result of further work there has been developed a new synthesis of steroid I based essentially upon the synthesis of Nagata et al. but working essentially with intermediates having A -unsaturation. Then new synthesis provides generally better yields and affords greater ease of working and purity of product, due essentially to the impossibility of epimerisation at position-17 in compounds of the A series.

Thus in accordance with the new synthesis 3a-hydroxy- Sa-pregnane-ILZO-dione is prepared by hydrogenation of 3a-hydroxy-5a-pregn-l6-ene-1 1,20-dione.

The hydrogenation may be conveniently effected in an organic solvent, for example an alkanol or an ether e.g. methanol, ethanol, propanol, diethyl ether or tetrahydrofuran. A catalyst is preferably used to effect the hydrogenation for example palladised charcoal, Raney nickel, platinum catalysts and the like.

3a-Hydroxy-h-pregn-l6-ene-l1,20-dione may, for example, be prepared by solvolysis of the 3a-acryloxy group of a 3a-acryloxy-5a-pregn-16-ene-l1,20 dione. The acyloxy group at the Bot-position may, for example, be a formyloxy, acetoxy, propionyloxy, butyryloxy or benzoyloxy group.

Advantageously, the solvolysis may be effected by hydrolysis, preferably under alkaline conditions although both acidic and alkaline hydrolyses may be used. The hydrolysis may, for example, be effected in the presence of a solvent such as an alkanol or an ether, e.g. methanol, ethanol, propanol, iso-propanol, butanol, t-butanol, diethylether, dioxan or tetrahydrofuran. The reaction may be effected at any convenient temperature, for example, at ambient temperature or an elevated temperature, ad vantageously at the boiling point of the solvent used. Suitable alkalis for the hydrolysis include, for example, alkali metal hydroxides e.g. sodium or potassium hydroxide.

The 30c acyloxy 5a pregn-16-ene-11,20-dione which may be used for the preparation of the corresponding 3a-hydroxy compound may, for example, be prepared from a corresponding 3,B-hydrocarbonsulphonyloxy-5apregn16-ene-l1,20-dione e.g. 35-tosyloxy-5a-pregn-16 ene-ll,20-dione and this reaction will be seen to be an inversion reaction in which the configuration as position-3 is changed from B to a.

According to this method, the 3/3-sulphonate may be reacted with the appropriate carboxylic acid in solution in a solvent medium to yield the desired 3u-acyloxy compound. This reaction is preferably effected in the presence of alkali metal ions it being convenient to use the carboxylic acid in the form of an alkali metal salt thereof e.g. the sodium or potassium salt. Suitable solvents include for example dimethylsulphoxide and N-alkylamide solvents, e.g. dimethylformamide and dimethylacetamide. Preferably the solvent is water miscible and contains water (for example up to 20%) which generally serves to accelerate the reaction. Advantageously the carboxylic acid is an aliphatic carboxylic acid, lower alkanoic acids being preferred, for example, formic, acetic, propionic or butyric acids or an aromatic carboxylic acid e.g. benzoic acid. Preferred salts are the sodium and potassium salts. Generally favourable results are obtained by the use of potassium acetate. The solvent used may be the carboxylic acid itself or an anhydride thereof (provided that such acid or anhydride is liquid at the reaction temperature) alkali metal ions being provided by an alkali metal salt e.g. of the carboxylic acid. For example when using aqueous formic acid, alkali metal ions which may be present may, for example, be provided by an alkali metal formate or an alkali metal hydrogen carbonate e.g. potassium formate or potassium hydrogen carbonate. The inversion of the configuration of the substituent at the 3-position of the 5a-pregn-l6-ene-l1,20-dione may be effected at any convenient temperature, advantageously at an elevated temperature, suitable conditions being found by preliminary experiment.

An alternative method of converting the above-mentioned 3/3-sulphonates to the corresponding 3a-hydroxy compounds involves treatment of the sulphonates under alkaline conditions using for example an alkali metal hydroxide, e.g. NaOH, in a polar solvent e.g. ethanol, methanol, dioxan etc.

The inversion of the configuration of the substituent from the 3B-position to the 3a-position may also be effected in the presence of dimethylformamide, or dimethylacetamide preferably in the presence of water e.g. analogous to the method described by Chang and Blickenstatf (J. Amer. Chem. Soc., 1958, 80, 2906), and Bharucha et al. (Can. J. Chem. 1956, 34, 982). This method when applied, for example, to the tosylate of 3fi-hydroxy-5w pregn-l6-ene-11,20-dione produced the corresponding 3a-formate together with some of the corresponding free hydroxy compound. Dimethyl acetamide may also be used, preferably under aqueous conditions, to form the 3u-acetoxy compound by inversion.

Zip-Hydrocarbon sulphonyloxy-5a-pregn-16-ene-1 1,20- diones may, for example, be prepared according to conventional methods. Thus the 3 3-hydroxy compound may be reacted with a hydrocarbon sulphonyl halide, for example p-toluene sulphonyl chloride, preferably in the presence of a tertiary base e.g. pyridine, collidine, N-methyl morpholine etc., the tertiary base, if desired, also acting as solvent. The sulphonylation reaction may, for example, be effected at a temperature of from 50 to 50 0., preferably to 25 C.

In carrying out the process for the preparation of 3u-hydroxy-5u-pregnane-11,20-dione, good overall yields from 3B-hydroxy-5a-pregn-16-ene-11,20-dione may be obtained by the omission of purificationof at least some of the intermediates. This process also has the advantage of comparative ease of purification of 3a-hydroxy-5apregnane-11,20-dione from the corresponding 3-desoxy compound formed as a by-product in the process from the corresponding 2,16-diene formed by elimination of the hydrocarbon sulphonyloxy group in the inversion step. Good overall yields from 3fl-hydroxy-5a-pregnane-l1,20- dione of high purity, may be achieved using potassium acetate in aqueous dimethylformamide in the inversion step. Improved results may be obtained by partial purification of the reactant used in the hydrogenation step.

3a-Hydroxy-5a-pregn-1'6-ene-11,20-dione may also be prepared by hydration of 5a-pregna-2,16-diene-l1,20- dione which may be formed by the elimination of the hydrocarbon sulphonyloxy group from the corresponding Bit-hydrocarbon sulphonyloxy compound. The hydration may, for example, be effected to the reaction with a mercury compound, preferably under acid conditions to form an oxymercurial intermediate which is then decomposed by reduction. For example, the oxymercuration may be carried out using mercuric acetate, mercuric sulphate or mercuric oxide in a solvent such as dioxan or tetrahydrofuran (preferably aqueous) advantageously in the presence of a strong acid e.g. perchloric acid, nitric acid, or sulphuric acid. Decomposition of the oxymercurial intermediate may for example be effected by reduction with an alkali metal borohydride e.g. sodium or potassium borohydride, preferably in the presence of aqueous alkali e.g. aqueous caustic soda.

3l3-Hydroxy-5u-pregn-16-ene-11,20-dione may beprepared from 3 3 acetoxy 5a-pregn-16-ene-11,20-dione (Chamberlin et al. J. Amer. Chem. Soc., 1951, 73, 2396). Hydrolysis of the 3,8-acetoxy compound may be effected by conventional methods, for example under alkaline conditions, e.g. in solution in acetone, an alkanol or ether such as methanol, ethanol, propanol, t-butanol, diethyl ether, dioxan or tetrahydrofuran. Suitable alkalis may, for example, be alkali metal hydroxides e.g. potassium hydroxide.

Steroids of general formula II above are new compounds. The preferred compounds of formula II for use as solubilising agents in pharmaceutical preparations are thosein which the 21-acyloxy group is a 21-acetoxy, 21- propionyloxy, 21-isobutryloxy or 21-benzoyloxy group.

The 2l-acyloxy compounds of formula II above may be prepared by any convenient method. However such com- III (in which R represents a hydroxy or protected hydroxy group e.g. a nitrate, trimethylsilyloxy or trichloroethoxycarbonyloxy group) with a lead tetraacylate preferably in the presence of a Lewis acid, and, where R represents a protected hydroxy group, subsequent conversion of said group to a hydroxy group. Protection of the 3oc-hYd1OXY group of the compound of formula HI however, is not essential before the acyloxylation reaction.

The lead tetra-acylate used may be for example lead tetraacetate. The Lewis acid may for example be boron trifiuoride, conveniently used as its etherate. We have found, for example that the presence of boron trifiuoride improves the rate of reaction and can enable lower temperatures of reaction to be employed, thus, in many cases, the reaction proceeds satisfactorily at ambient temperature, i.e. in the absence of applied heat.

The yield obtained by this process is frequently better than that obtained at an elevated temperature in the absence of boron trifiuoride and the fact that the reaction rate is faster and thus lower temperatures can often be used means that this process possesses economic advantages on the large scale. The ability to operate at lower temperatures also means that there may be less likelihood of undesired side reactions taking place.

The acyloxylation of compounds of the formula III may be carried out in a solvent medium comprising a mixture of a hydrocarbon solvent and an alcohol. Suitable hydrocarbon solvents are, for example, benzene or toluene and the alcohol may, for example, be methanol. Advantageously the solvent comprises a mixture of benzene and methanol in the ratio of 19:1.

The acyloxylation is especially suitable for acetoxylation using lead tetraacetate but other lead acylates, e.g. lead tetrapropionate may, of course, be used with the formation of the corresponding 21-propionyloxy compound.

The 3ot-trimethylsilyloxy compounds of formula HI (R representing a trimethylsilyloxy group) may, for example, be prepared by the reaction of the parent 3ahydroxy compound of formula III (R' representing a hydroxy group) with a trimethylsilyl halide e.g. trimethylchlorosilane or hexamethyl disilazane in the presence of a tertiary base e.g. pyridine and, if desired, in the presence of a solvent e.g. a halogenated hydrocarbon such as methylene chloride or tetrahydrofuran. The reaction may conveniently be effected at room temperatures or if desired, at lower temperatures e.g. 0 C. The trimethylsilyloxy protecting group is generally automatically removed during the acyloxylation.

The 3a-trichloroethoxycarbonyloxy compound of formula III may be prepared by reaction of the parent 3a-hydroxy compound with an alkylchloroformate, e.g. trichloroethyl chloroformate, preferably in the presence of an acid binding agent e.g. a tertiary amine such as pyridine, conveniently in a solvent such as dioxan or tetrahydrofuran. The trichloroethoxy carbonyl protective group may subsequently be removed by reduction for example using a metal/acid system such as zinc and acetic acid.

The Zia-nitrate of formula III may be prepared by reaction of the parent 3u-hydroxy compound with fuming nitric acid and acetic anhydride preferably in the presence of a solvent e.g. chloroform. The nitrate protection group may subsequently be removed by reduction, for example, using a metal acid system such as zinc and acetic acid or catalytic hydrogenation using for example, palladium on charcoal as catalyst.

Other methods for the preparation of the 21-acyloxy compounds of formula II above may also 'be used. Thus a 2l-acyloxy-5a-pregnane-3,11,20-trione may be reduced, for example, using an enzymatic method such as reduction with brewers yeast (Saccharomyces cerevisiae). This method is convenient for the preparation of 2l-alkanoyloxy compounds such as the 21-acetoxy compound.

Compounds of formula II may also be prepared via the corresponding 21-chloro, 2l-bromo or 21-iodo compounds. We prefer to proceed via the 2l-bromo intermediate which may be prepared from 5oz-pregnan-3a-ol- 11,20dione. The bromination is effected for example using molecular bromine, in a solvent such as methanol or ethanol advantageously at a temperature of from to +30 C. The reaction is preferably conducted in the presence of a catalyst such as acetyl chloride or hydrogen bromide in acetic acid. The 21-halogeno compound may then be converted into the desired 21-acyloxy compound by reaction with the salt of the corresponding carboxylic acid, such as an alkali metal salt e.g. the potassium salt or a tertiary amine salt conveniently N- methylmorpholine or N-ethylpiperidine or a trialkylammonium salt e.g. the triethylammonium salt. The reaction is preferably carried out in a solvent for example acetone or methanol, advantageously under anhydrous conditions.

An alternative method, particularly convenient for the preparation of compounds of the formula II in which R is other than an acetyl group, comprises acylating a compound of formula H IV (wherein R represents a protected hydroxy group) and deprotecting the 3a-hydroxy group of the 21-acyloxy derivative of the compound of formula IV produced. The compound of formula IV is conventiently prepared by the deacylation of a 21-acyloxy derivative of a compound of formula IV, for example a 21-acetoxy derivative thereof, and provides a method for converting one compound of formula II for example in which R is acetyl to another compound of formula II in which R is a different acyl group. The 2l-acetyl compound of formula II may thus, for example, be converted into another 21-acyl compound of formula II by firstly protecting the 3OL-hydroxy group with a protecting substituent which may be removed under acidic, reductive or other conditions but is stable under alkaline conditions, such as a 3a-ether substituent e.g. a tetrahydropyranyl or triphenylmethyl substituent or preferably a 3a-nitrate ester, hydrolysing the 3a-protected compound to yield the corresponding 2l-hydroxy compound, under basic conditions, preferably in the presence of potassium or sodium hydrogen carbonate, conveniently in the presence of a solvent e.g. methanol, ethanol or tetrahydrofuran, reesterifying the resultant product and removing the 3a-protecting substituent.

The reesterification is preferably effected using the anhydride or chloride of the desired acid preferably in the presence of a tertiary amine (e.g. pyridine, collidine, or dimethylaniline) which may also serve as solvent for the reaction.

The protecting group at position 3 may be removed in conventional manner, conditions may be chosen which will not effect the rest of the molecule. Thus for example COCHzOH when the Zia-hydroxy group of the compound of formula II is protected 'by the formation of a nitrate ester, the nitrate group may be removed by acid hydrolysis of the compound for example using aqueous mineral acid, or by reduction using, for example zinc and acetic acid or by catalytic hydrogenation using, for example, palladium on charcoal as catalyst.

The following examples are given by way of illustration only, all temperatures being in degrees centigrade.

EXAMPLE 1 3 fl-Hydroxy-S u-pregn-16-ene-1 1,20-dione A solution of 3fi-acetoxy-5a-pregn-16-ene-11,20-dione (Chamberlin et al., J. Amer. Chem. Soc., 1951, 73, 2396) (25.7 g.) in dioxau (Analar, 500 ml.) was treated with potassium hydroxide (10 g.) and water 250 ml. and the mixture allowed to stand at room temperature for 1 hour. After a further 1 hour at 40 the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina (ca. g.). The material obtained was crystallised from acetone-petroleum to give pure BB-hYdIOXY-Sa-Pffigll-16-61'16-11,20-di01'1e (17.65 g., 77.5%) as small plates, m.p. 2l7.5, [04 +82.9 (c. CHCl 1.1), Amax 234 nm. (e 10,10). (Found: C, 75.9; H, 9.3. C H O requires C, 76.3; H, 9.2.)

Example 2 3 ,B-Toluene-p-sulphonyloxy-5 a-pregn-16-ene-1 1,20-dione A solution of 3/3-hydroxy-5u-pregn-16-ene-l1,20-dione (39.6 g.) in dry pyridine (165 ml.) was treated with toluene-p-sulphonyl chloride (43.9 g.) to give the toluene sulphonate (56.7 g.), m.p. 147-151. A portion (10.7 g.) of this material was crystallised from ethyl acetate-petroleum to give the pure toluenesulphonate (9.2 g.) as plates, mp. 154-155", M +423 (c., cHc1 1.2), x,,,,,. 226 nm. (e 20, 780). (Found: C, 69.6; H, 7.4; S, 6.5. C H O S requires C, 69.45; H, 7.5; S, 6.6%.)

EXAMPLE 3 3 a-HydmXy-Sa-pregn-16-ene-1 1,20-dione A solution of 3 S-toluene-p-sulphonyloxy-5a-pregn-l6- ene-ll,20-dione (19.1 g.) in N,N-dimethylformamide (160 ml.) and water (16.0 ml.) was treated with potassium acetate (29.2 g.) and the mixture heated at (complete solution on heating) for 2 /2 hours. The solvents were removed in vacuo and the residue partitioned between chloroform and water. The chloroform extract was washed with water, dried and evaporated. The residue was taken up in methanol (500 ml.) and the solution flushed with nitrogen. Potassium hydroxide (17 g.) in water (70 ml.) was added and the solution refluxed for 1 hour. Glacial acetic acid was added to bring the pH to about 6 and most of the methanol evaporated in vacuo. Dilution with water gave a gummy precipitate which was extracted into chloroform to give the crude product. This material was extracted with ether and the residue boiled with benzene. The insoluble material was crystallised from chloroform-petroleum to give 3a-hydroxy-5upregn-l6- ene-11,20-dione (3.28 g.) as large prisms, mp. 243-244, [ab +86.5 (c., CHCl 0. 8), k 233 (6 9,530). (Found: C, 76.6; H, 9.2. C H O requires C, 76.3; H, 9.15%.)

Example 4 3a-I-Iydroxy-5a-pregnane-11,20-dione From 3a-hydroxy-5a-pregn-16-ene-11,20dione: A solution of 3ot-hydroxy-5a-pregn-16-ene11,20-dione (200 mg.) in freshly distilled tetrahydrofuran (8 ml.) with 5% palladium on carbon (100 mg.) was hydrogenated till hydrogen uptake ceased. The mixture was filtered through a pad of kieselguhr and the tetrahydrofuran removed in vacuo to give 3a-hydroxy-5a-pregnane-11,20-dione 13 (196 mg.), m.p. 171-172: [oc] +1125 (c., cncl 1.0

EXAMPLE 3a-Hydroxy-5a-pregnane-1 1,20-dione A solution of 3fi-acetoxy-5a-pregn-16-ene-11,20-dione (50 g., 0.134 mole) in dioxan (1,050 ml.) was flushed with nitrogen and treated with potassium hydroxide g., 0.356 mole) then nitrogen flushed water 535 ml.). The solution was stored at 40 for 1 hours then at room temperature for 1 hour. Glacial acetic acid was added (to pH ca. 7), the organic solvent removed in vacuo until crystallisation started and the resulting mixture diluted with water (ca. 1,500 ml.). The precipitated solid was filtered off, washed with water (until washings were neutral) and dried over phosphorus pentoxide in vacuo. This gave the alcohol (39.9 g., 90% theory) as an 011- white crystalline solid m.p. 216-218, [a] +82.9 (c. 1.0, CHCl Amax, 234 nm. (6 9,210).

An ice-cold solution of toluene-p-sulphonyl chloride (96 g., 0.505 mole) in dry pyridine (180 ml.) was added to an ice-cold solution of the above alcohol (86 g., 0.26 mole) in dry pyridine (180 ml.). The dark orange solution was allowed to warm to room temperature and kept at that temperature for 16 hours. The mixture was cooled at 0 and sufiicient water (ca. 20 ml.) added to dissolve the precipitated pyridine hydrochloride. The clear solution was kept at room temperature for 2 hours then diluted with ZN-hydrochloric acid (2.5 1.). The precipitated crystalline solid was filtered ofif, washed with ZN-hydrochloric acid (500 ml.) then water (until washings were neutral) and dried in vacuo over phosphorus pentoxide to give the tosylate (120 g., 95%), m.p. 147 150 decomp., [ab +38.6 (c. 1.0, CHCl A mixture of the tosylate (60 g.; 0.124 mole) in N,N- dimethylformamide (350 ml. and potassium acetate (92 g., 0.94 mole) in water (35 ml.) was stirred at 115 for 4 hours. The brown solution was cooled and most of the N,N-dimethylformamide removed by evaporation at 50 and 4 mm. to give a brown solid mass. Another run with tosylate (58 g., 0.12 mole), potassium acetate (90 g. 0.91 mole), N,N-dimethylformamide (350 ml.) and water (35 ml.) was carried out as described above. The combined residues were shaken with chloroform, the chloroto bring the pH to about 7 and two thirds of the solvent was removed by distillation in vacuo (water pump). Water (ca. 3 l.) was added to the resultant mixture (which had already begun to crystallise) and the precipitated solid was filtered 0:, washed with water and dried over phosphorus pentoxide to give the crude Zia-alcohol (73.9 g.).

A solution of the above crude alcohol (73.8 g.) in tetrahydrofuran (1900 ml., freshly distilled) with 5% palladised charcoal (25 g.) was hydrogenated at atmospheric pressure and room temperature. after 1% hours hydrogen uptake (ca. 71) ceased. The catalyst was filtered oil on a kieselguhr pad and the filtrate was concentrated in vacuo to a crystalline mass (71.3 g.).

This material was dissolved in chloroform and filtered through a column of grade III neutral alumina (150 g.) which was washed with chloroform (total ca. 400 ml.). The chloroform was removed in vacuo and the residue taken up in acetone (200 ml.). Acetone (100 ml.) was boiled off and the solution was diluted (with stirring with petroleum (ca. 2 1.). The precipitated solid was collected by filtration, washed with petroleum and dried to give the crude alcohol (47.1 g.) m.p. 161163. Retreatment with acetone-petroleum gave material (38.3 g.) m.p. 165- 168 and a second crop (3.0 g.) m.p. l67168 as fine needles. A further treatment of these combined crops atforded purer material (33.8 g. plus a 5.3 g. second crop) m.p. 168-169 (97.2% pure on G.L.C., 45.5% yield based on 3/8-alcohol). A final treatment gave 30:- hydrOXy-Swpregnane 11,20-dione (35.1 g., 40.8% yield based on 115-alcohol; 46.7% yield based on 3,8-acetate) as needles m.p. 168-170 [11] +111.6 (c. 1. 0, CHCl (Found: C, 76.15; H, 9.6; Calcd. for C H O C, 75.9; H, 9.7%.) Purity by G.L.C. analysis was 97.7%.

Chromatography of the combined residues on grade III neutral alumina gave a further amount (9.3 g.) of 3a-hydr0xy-5a-pregnane-1 1,20-dione.

EXAMPLES 6-16 The table records gas-liquid chromatographic analysis of mixtures of 3a-acetoxy (and/ or formyloxy)-5a-pregn- 16-ene-11,20-dione, 30c hydroxy 5a-pregn-6-ene-11,20- dione and 5u-pregn 2,16-diene 11,20-dione formed by solvolysis of 3Btoluene-p-sulphonyloxy-5a-pregn-16-eneform layer separated and washed with more water (ca. L

Displacement reactions on 3B-to1uene-p-sulphonyloxy-fia-pregn-lfi-ene-ll,20-dione Weight 01 Percent Total percent Per- Ex. tosylate Other 3|1-CH C02 Percent 3(1-CH3C02 cent No. (g.) Solvent volume (ml.) reactants (g.) Time (hrs.) mP-, +3aHC0z Sa-OH +3a0H A 6. 0. 56 D.M.F., 10 1 111003, 64 3 11 43. 7 12- 8 56. 5 39. 5 7..- 1. 9 D.M.F., 75, E 0 46% then 5 then 18%.- 80-90-100 64. 5 14. 1 78. 6 21. 4 s- 0. 58 D.M.F., 15, E20, 0.33. a 115 52. a 20. 5 72.8 27. 2 9- 0. 532 D.M.F., 15, B20, 1.2--.- HCOzK, 0.566--.. 21 then 5 80-90 27.3 39. 4 66. 7 19. 7 10-. 0. 532 D.M.F., 15, Hr 1.2 HCOzK, 0.566-.- 3 115 53. 6 21. 9 75. 5 24. 5 11- 0. 532 D.M.F., 15, 13:0, 1.2.... HCOzK, 0.566.-- 3%--. 0 7 8 71- 5 5 12---- 0. 532 D.M.F., 15, H20, 1.2 HCOzK, 0.566... 100 0 3 6 69. 6 28. 0 13. 0. 532 D.M.F., 15, E20 1.2--.- KOAc, 0.66 80-90 53. 4: 21. 5 74. 9 25. 1 14- 60. 0 D.M.F., 350, H 6 35..-. KOAc, 92 0 115 59. 7 14.7 74. 4 23. 7 16.- 0. 532 D.M.F., 15, Hz 115 59. 3 10. 3 69. 6 27. 5 16 0. 486 HCOrH, 20, H 100 44. 1 1. 9 46. 0 49. 6

200 ml. The combined aqueous fractions were extracted EXAMPLE 17 with chloroform (3 X 100 ml.) and the combined chloroform extracts (including those above) were washed with water (3X 100 ml.) and dried over magnesium sulphate. The chloroform was removed in vacuo and residual N,N-dimethylformamide was evaporated at and 4 mm. to give the crude 3a-acetate (92 g.) as a brown solid.

A solution of the crude acetate (92 g.) in dioxan (1,000 ml.) was mixed with a solution of potassium hydroxide (45 g., 0.8 mole) in water (500 ml.) to give a two-phase system. A homogeneous solution was obtained by the addition of dioxan (440 ml.) and water (625 ml.). Nitrogen was bubbled through the solution which was heated at 50 for 2 hours. The port coloured 3a-Hydroxy-5a-pregn-16-ene-1 1,20-dione 5a-Pregna-2,16-diene-11,20-dione (700 mg, 2.2 mmole) was dissolved in tetrahydrofuran (10 ml.), and water (4 ml.) was added. Mercuric acetate (700 mg., 2.2 mmole) was added to the stirred solution to give an immediate yellow precipitate. The reaction mixture was stirred at room temperature for 24 hours, and then 3M sodium hydroxide solution (3 ml.) and 0.5M sodium borohydride in 3M sodium hydroxide solution (about 3 ml.) were added until all the yellow complex had been reduced. The tetrahydrofuran layer was separated, washed with sodium chloride solution, and then diluted with ether (100 ml.). The organic solution was washed well with water, dried, and

solution was treated with glacial acetic acid (ca. 40 ml.) evaporated to give a white oily solid, which was purified by preparative thin-layer chromatography and recrystallisation from ethyl acetate/petroleum to give 3a-hydroxy- 5a-pregn-16-ene-11,20-dione (160 mg, 22%) as colourless crystals, m.p. and mixed m.p. with an authentic sample, 234-237, [a1 +86.5 (c.1.1CHCl EXAMPLE 18 21-Acetoxy-3 a-hydroxy-5 u-pregnane- 1 1,20-dione Boron trifluoride etherate (37.9 ml.) was added to a stirred solution of 3a hydroxy-Sa-pregnane-,20-dione (6.64 g., 20 mmole) and lead tetraacetate (10.1 g., 22 mmole) in dry benzene (280 ml.) and methanol (15.1 ml.) at room temperature. After 2 hours the mixture was poured into water (2 l.) and extracted with ether (1 1.). The combined ether extracts were washed successively with sodium bicarbonate solution and water, dried over magnesium sulphate, and concentrated in vacuo to give a white crystalline mass. Four recrystallisations from acetone-petroleum (b.p. 40-60") gave 21 acetoxy-3a-hydroxy 5a-pregnane-11,20-dione as fine needles (4.22 g., 54%), m.p. 172-173, [01] +104 (c. 1.0: CHCl (Found: C, 70.8; H, 8.9; C H O requires C, 70.8; H, 8.8%.)

EXAMPLE 19 21-Acetoxy-3ot-hydroxy-5a-pregnane-11,20-dione via a trimethylsilyl derivative Trimethylchlorosilane (0.33 ml., 1.5 equiv.) and pyridine (0.485 ml., 2 equiv.) were added to a solution of 3ahydrQxy-S-a-pregnane-I1,20-dione (1.0 g.) in methylene chloride (16.6 ml.) at room temperature. After 16 hours at more trimethylchlorosilane (0.33 ml., 1 equiv.) was added and after a further 1 /2 hour the solvent was removed in vacuo. Ether was added to the residue and the white solid was filtered off. The ether was removed in vacuo and the residue triturated with a little petroleum (b.p. 40-60) to give 3a-trimethyl-siloxy-5a-pregnane-11, 20-dione (0.2 g.), m.p. 95-96. This compound was also prepared by the use of hexamethyldisilazane and trimethylchlorosilane in tetrahydrofuran.

The 21-acetoxylation was carried out as described in Example 18, one crystallisation from acetone-petroleum (b.p. 40-60") afforded the 21acetate, m.p. 170473.

EXAMPLE 20 21-Acetoxy-3a-hydroxy-5u-pregnane-11,20-dione via a trichloroethoxycarbonyl derivative 2,2,Z-Trichloroethylchloroformate (1.1 ml.) was added' to a cooled, stirred, solution of 3a-hydroxy-5a-pregnane 11,20-dione in pyridine (0.74 ml.) and dioxan (5.6 ml.) After 10 minutes dilute hydrochloric acid (14.5 ml.) was added and the solution was heated at 100 for 30 minutes. The resulting oil crystallised on cooling to give 3a-(2,2,2- trichloroethoxycarboyloxy) a pregnane 11,20-dione (1.45 g.), m.p. 130131, [aJ +56 (c. 1.0, CHCl (Found: C, 56.0; H, 6.5; Cl, 21.1; C H Cl O requires C, 55.6; H, 6.6; Cl, 20.7%.)

21-Acetoxylation of this compound (0.5 g.), using the procedure described in Example 18 gave a syrupy residue that crystallised on the addition of ether and petroleum. Recrystallisation from ether-petroleum (b.p. 40-60) gave 21 acetoxy-3a-(2,2,2-trichloroethoxycarbonyloxy)- 5a-pregnane-11,20-dione (0.35 g.), m.p. 143-146 (decomp), [od +75.2 (c. 1.0, CHCl (Found: C, 55.1; H, 6.0; Cl, 18.6. C H Cl O requires C, 54.3; H, 6.4; CI, 19.2%.)

Removal of the 2,2,Z-trichloroethoxycarbonyl group was effected by stirring a solution of the steroid (0.10 g.), in ethanol (2 ml.) and glacial acetic acid (2.5 ml.) for 5 hours with addition of zinc dust (0.3 g.) during this period. The solids were filtered off, washed with ethanol and the combined filtrate was reduced in volume in vacua. I

16 EXAMPLE 21 21-Acetoxy-5a-pregnan-3u-ol-11,20-dione Dried yeast (Saccharomyces cerevisiae 50 g.) was stirred at room temperature with tap water (2 1.) containing sucrose (200 g.) and di-ammonium hydrogen phosphate (4 g.). After two hours 21-acetoxy-5a-pregnane-3, 11,20-trione (1 g.) (Mancara et al., J. Amer. Chem. Soc., 1955, 77 5669) in ethanol ml.) was added. The fermentation was stirred at room temperature for a further 24 hours, the yeast was removed by filtration, partially dried at the pump and extracted with hot chloroform (4x 250 ml.). The extracts were shaken with the filtrate, washed with water, dried (Na SO' and evaporated to a brown gum (634 mg.). This was subjected to preparative thin-layer chromatography which yielded two pure substances. Of these the less polar was the starting material 21 acetoxy-5a-pregnane-3,11,20-trione, (68 mg.); which was recrystallised from acetone/hexane as colourless needles, m.p. 169-172; [11] +127.5 (c. 0.87 CHCl Gas-liquid chromatography confirmed that this was identical with the starting material.

The more polar substance (70 mg.) was recrystallised from acetone/hexane to afford 2l-acetoxy-5ot-pregnan-3a- 0l-11,20-di0ne (57 mg.) as colourless needles, m.p. 179- 182; [0:1 +107, (c. 1.09 CHCl Gas-liquid chromatography confirmed the identity of this material.

EXAMPLE 22 21-Acetoxy-5u-pregnan-3a-ol-11,20-dione (a) 21 Bromo-5a-pregnan-3uol-11,20-dione: Sat-Pregnan-3a-ol-11,20-dione (1 g., 3 mmoles) in stirred methanol (7 ml.) at 30 was treated with acetyl chloride (1 drop). After two minutes bromine (0.19 ml., 3.52 mmoles) in methanol (4.5 ml.) was added dropwise, the solution being allowed to decolourise between the addition of each drop. The resulting clear solution was poured into chloroform (100 ml.), washed with water (3X 50 ml), dried (Na SO and evaporated to a white froth (1.40 g.). Preparative thin-layer chromatogaphy afforded 21-bromo- Sa-pregnan-Sa-Ol-l1,20-dione (715 mg.) which crystallised from chloroform/ether as clusters of colourless needles, m.p. -163; [ab +109 (c. 0. 82, CHCl (Found: C, 61.0; H, 7.9; Br, 19.7; C H BrO requires C, 61.3; H, 7.6; Br, 19.45%.)

A second, unstable substance (415 mg.) isolated from this reaction was examined spectroscopically andidentified as 17a-bromo-5u-pregnan-3a-ol-l1,20-dione.

(b) 21 Acetoxy 5oz pregnan-3a-ol-11,20-dione: 5a- Pregnan-3a-ol-l1,20-dione (1 g. 3 mmoles) was brominated in the manner described above. The total product from the reaction (1.38 g.) was refluxed with stirring with dry acetone (25 ml.) and anhydrous potassium acetate (2 g.). After four hours the reaction mixture was poured into chloroform (100 ml.), washed with water '(3 50 ml.,) dried (Na SO and evaporated to a white froth (1.19 g.). Preparative thin-layer chromatography afforded 21-acetoxy-5a-pregnan-3a-ol-l1,20-dione (634 mg.) as a white froth which on crystallization from acetone/ether gave colourless needles, M.P. 177180; [111 +102.5, (c. 0.95, CHCI Gas-liquid chromatography confirmed the identity of this material.

EXAMPLE 23 21-Acetoxy-5a-pregnan-3a-ol-11,20-diene 5a-Pregnan-3a-ol-11,20-dione (5 g., 15.0 mmoles) in stirring until the colour disappeared and then poured into of a 50% w./v. solution of hydrogen bromide in glacial acetic acid. After several minutes, bromine (0.95 ml., 2.815 g. 17.6 mmoles) in methanol (22.5 ml.) was added portionwise over ca. 10 minutes. The solution was left stirring until the colour disapeared and then poured into water. The product was isolated by filtration, washed with water and dried in vacuo at 40 for five hours. Final drying was over phosphorus pentoxide in a desiccator (overnight). Yield: approximately quantitative.

The crude bromo-intermediate was dissolved in acetone (.100 ml., dried over potassium carbonate) and refluxed in the presence of potassium acetate (10 g.) for four hours.

The reaction mixture was poured into water (1 l.) and extracted with ether (300 ml. and 250 ml.). The ether was dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure.

The residual foam was recrystallized from acetonepetroleum ether to give 21-acetoxy-5a-pregnan-3a-ol-11,

20-dione as white needles. Yield, 63%; M.P. 173175; [aJ +109 (c. 1.0, CHCl EXAMPLE 24 5a-Pregnan-3a-ol 11,20 dione (2 g., 6 mmoles) in methanol (14 ml.) at 30 was treated with acetyl chloride (2 drops). The solution was stirred for two minutes and was treated dropwise with bromine (0.38 ml., 7 mmoles) .in methanol (9 ml.) in the manner described above. The

thin-layer chromatography afforded material which on recrystallization from chloroform/ether/hexane gave 21- propionyloxy-5a-pregnan-3a-ol-l1,20-dione (589 mg.) as colourless irregular prisms, m.p. 159170; [01] +99,

'(c. 0.92, CHCl (Found: C, 70.5; H, 8.9. C H O lAH O requires C, 70.45; H, 9.0%.)

EXAMPLE 25 21-Isobutyryloxy-5u-pregnan-3a-ol-l 1,20-dione 5m Pregnan 3a-o1-11,20-dione (2 g., 6 mmoles) in methanol (14 ml.) at 30 was treated with acetyl chloride ('2 drops). The solution was stirred for two minutes before being treated dropwise with bromine (0.38 ml., 7 mmoles) in methanol (9 ml.) in the manner described above. When the reaction was complete the solution was poured into stirred water (250 ml.). The product was isolated, washed .anddried at thepump. A final drying over phosphorus pentoxide in .vacuo afforded a white powder (2.5 g.). This was refluxed with isobutyric acid (14.1 ml., 0.15 mole) and triethylamine (7.25 ml., 0.10 mole) in dry acetone (60 ml.). After four hours the solution was poured into chloroform (300 ml.), washed with aqueous potassium hydrogen carbonate (2 200 ml.), with water (2 200 ml.), dried (Na SO and evaporated to a white froth (2.54 g.). Preparative thin-layer chromatography afforded 21-isobutyryloxy-5a-pregnan-3a-ol-l1,20-dione (1.45 g.) as a white froth, [a] +93.5, (c. 0.66, CHC1 (Found: C, 70.4; H, 8.8. C H O /2 H O requires C, 70.25; H,

EXAMPLE 26 21-Benzoyloxy-5a-pregnan-3u-ol-l 1,20-dione 5a Pregnan 3oz-O1-11,20di0116 (2 g., 6 mmoles) in methanol (14 ml.) was treated with acetyl chloride (2 drops) and bromine (0.38 ml., 7 mmoles) as described above. Isolation of the crude bromination product in the usual manner afforded a white powder (2.498 g.). This was refluxed with benzoic acid (18.3 g., 0.15 mole) and triethylamine (7.25 ml., 0.1 mole) in dry acetone (100 ml.). After five hours the solution was poured into chloroform (500 ml.), washed with aqueous sodium hydrogen carbonate (2X 200 ml.) and with water (3X 200 ml.), dried (Na SO and evaporated to a white froth. Preparative thin-layer'chromatography afforded 21-benzoyloxy- 18 5a-pregnan-3a-ol-11,20-dione (1.27 g.) as a white froth, [a] +104, (c. 0:65, CHCI (Found: C, 72.6; H, 7.7. C H O V2H O requires C, 72.85; H, 8.05%.)

EXAMPLE 27 21-Isobutyryloxy-5a-pregnan-3u-ol-l1,20-dione 3-nitrate (i) Fuming nitric acid (1.3 ml.) was added to stirred acetic anhydride (5 ml.). The solution was cooled to -5 and 21 acetoxy 5oz pregnan 3a ol 11,20- dione (500 mg. 1.28 mmoles) in chloroform (2.5 ml.) was added. The resulting solution was stirred at 5 for an hour before being poured into dilute aqueous sodium hydroxide ml.), extracted with chloroform (2 75 ml.) and the extract washed with aqueous sodium bicarbonate (50 ml.), with water (3X 50 ml.), dried (Na SO and evaporated to a gum (527 mg). Crystallization from ether/acetone afforded 21-acetoxy-5u-pregnan-3u-ol-11,20-dione 3-nitrate (386 mg.) as colourless needles, m.p. 147149; [a] +103 (c. 1.06, CHC1 (Found: C, 63.6; H, 7.5; N, 3.1. C H NO requires C, 63.45; H, 7.65; N, 3.2%.)

(ii) 504 Pregna 3u,21-diol-11,20-dione 3-nitrate: (a) 21-Acetoxy-5a-pregnan-3a-ol-11,20-dione 3-nitrate (837 mg., 2 mmoles) in ethanol (42 mg.) and tetrahydrofuran (42 ml.) was stirred with 10% aqueous potassium hydrogen carbonate (4 ml.) and 2 N aqueous sodium hydroxide (2 ml.). After three hours glacial acetic acid (1 ml.) was added, the solution was poured into water (400 ml.) and extracted with chloroform (3X ml.). The extracts were washed with water (2 50 ml.), dried (MgSO and evaporated to a froth. Preparative thin-layer chromatography afforded pure material which on recrystallization from ether/acetone gave 5a-pregna-3a,21-diol-11,20-dione 3-nitrate (219 mg.) as colourless irregular prisms, m.p. 172-176; [u] +91 (c. 0.97, CHCl (Found: C, 63.9; H, 7.8; N, 3.5 C H NO requires C, 64.1; H, 7.95; N, 3.55%.)

(b) 21-Acetoxy-5a-pregnan-3a-ol-11,20-dione (5 g., 13.3 moles) in chloroform (25 ml.) was added to a stirred solution of fuming nitric acid (13 ml.) in acetic anhydride (50 ml.) at 5. The reaction mixture was stirred at --5 for :an hour, poured into stirred aqueous sodium hydroxide (1 l.) and extracted with chloroform (2 200 ml.). The extract was washed with aqueous sodium hydrogen carbonate 100 ml.) and with water (2 100 ml.), dried (Na SO and evaporated to a white froth. This was dissolved in methanol (500 ml.), the solution flushed with nitrogen and stirred with 10% aqueous potassium hydrogen carbonate (17.5 ml.) for four hours. Glacial acetic acid (3 ml.) was added, the solution evaporated to small bulk, poured into water (1 l.) and extracted with chloroform (2 200 ml.). The extract was washed with water (2 100 ml.), dried (Na SO and evaporated to a white froth. Crystallization from acetone ether gave Sat-pregna- 3a,2l-diol-l1,20-dione 3-nitrate (4.31 g.) as colourless irregular prisms, m.p. 174-181.

(iii) 21-Isobutyryloxy-5a-pregnan-3a-ol-11,20-dione 3- nitrate: 5u-Pregna-3a,21-diol-11,20-dione 3-nitrate (2.0 g., 5.08 mmoles) in dry pyridine (20 ml.) was treated with isobutyryl chloride (2 ml.). The pink solution was allowed to stand at room temperature for 20 hours before being poured into stirred water and acidified with dilute hydrochloric acid. The product was isolated, washed thoroughly with water and dried at the pump. Recrystallisation from acetone/hexane afforded 21-isobutyryloxy-5u-pregnan-3a-ol-11,20-dione 3-nitrate (1.01 g.) as colourless needles, m.p. 167-169; [od +97.5, (c. 1.48, CHCl (Found: C, 64.5; H, 7.8; N, 3.2. C25H37NO7 requires C, 64.8; H, 8.05; N, 3.0%.)

(iv) 21 Isobutyryloxy-Su-pregnan-3u-ol-11,20-dione: 21-Isobutyryloxy-5a-pregnan-Ba-OI-11,20-dione 3 nitrate (1.35 g., 2.91 mmoles) in glacial acetic acid (35 ml.) was stirred for an hour at room temperature with zinc powder (4 g.). The zinc was removed, washed with hot chloroform (200 ml.) and the combined washings and filtrates were washed with water (4x 100 ml.) dried (Na SO and evaporated to a white froth. Preparative thin-layer chromatography afiorded 2l-isobutyryloxy-5rxpregnan-3a-ol-1l,20dione as a white froth, [th, +97.5 (c. 1.05; CHCl Analytical thin layer chromatography and gas-liquid chromatography indicated that this material was identical with a sample prepared by the method described in Example 25.

EXAMPLE 28 3u-Hydroxy-5u-pregn-16-ene-l1,20-dione and Set-Pregna- 2,16-diene-1 1,20-dione A stirred mixture of 3,B-toluene-p-sulphonyloxy-Sorpregn-16-ene-11,20-dione (627 g.), potassium acetate (918 g.), dimethylformamide (4.25 l.) and water (425 ml.) was heated on the steam bath for 4 hr. Most of the dimethylformamide was removed under reduced pressure and water was added to the residue with stirring. The solid (420 g.) was collected, washed and dried at 40 in vacuo. This material in peroxide free dioxan (7 l.) was flushed with nitrogen and a solution of potassium hydroxide (200 g.) in water (2 l.) was added. The mixture was stirred and heated at 50-60 for 7 hrs. and then left at room temperature overnight. Acetic acid (50 ml.) was added and the precipitated solid filtered off, washed with water and dried. The dry solid was heated under reflux with benzene (2 l.) for 2 hrs. the mixture cooled and filtered to give 3a-hydroxy-5a-pregn-16-ene-11,20-dione (215 g.).

Benzene extracts from several similar experiments were combined and evaporated. The crude solid was redissolved in hot benzene and petroleum (b.p. 6080) was added until the solution was just clear at ambient temperature (an insoluble residue was removed by filtration at this stage). The clear solution was passed down an alumina column (Woelm alumina, activity grade I) previously prepared with benzene-petroleum (b.p. 60- 80) in the ratio 6:4. Elution with the same solvent gave the diene. Elution was terminated when thin layer chromatography indicated the presence of slower running components in the eluate. The combined fractions were evaporated and twice crystallised from benzene-petroleum (b.p. 60-80) to give a-pregna-2,16-diene-11,20-dione as colourless crystals, m.p. 176-177, [11] +159 (c., 1.0 in CHCl A (EtOH) 233.5 nm. (e 9150). (Found: C, 80.5; H, 8.9; C H O requires C, 80.8; H, 9.0%.)

EXAMPLE 29 5a-Pregna-3u,21-diol-11,20-dione 21-hemisuccinate .ml.), dried (Na SO and evaporated to a white froth.

Crystallisation from benzene/hexane/ chloroform gave 5 ocpregna-3u,2l-diol-l.l,20-dione 21 hemisuccinate (800 mg.) as colourless needles, m.p. 166168; [041 +90.5 (0. 1.32m CHCl (Found: C, 66.9; H, 8.0. C H O requires C,-66.95; H, 8.1%.)

. The starting'material-for this preparation was obtained from 5a-pregna-3u,21-diol-11,20-dione 3-nitrate (see Example 27(ii)) as described below:

5u-Pregna-3a,21-diol-11,20-dione 3-nitratc (2 g., 5.08 mmoles) and succinicanhydride (2 g. 20 mmoles) in dry pyridine (20 ml.) were allowed to stand at room temperature for 18 hours. The solution was poured into stirred water (300 ml.) which was then acidified. After two hours, the precipitate was-collected, washed well with water and dried. Recrystallisation from benzene/hexane 20 H, 7.3; N, 2.6. Cz5H 5NO requires C 160.8; H, 7 15; 2.85%.)

EXAMPLE 30-AQUEOUS soLU'r-IoN EXAMPLE 3lAQUEOUS SOLUTION 0.035 g. of steroid I reduced in size asin Example 30 are mixed with 0.035 g. of steroid II(R" '-CH CO-') reduced in size as for steroid I. The steroids are added to 10 ml. of a 20% w./v. (200 mg./rnl.) solution'of Cremophor EL containing 0.025 g. of sodium chloride and the mixture mechanically stirred for at least 24 hours; Any traces of insoluble residue are filteredofi using a sintered glass filter.

EXAMPLE 32 AQUEOUS SOLUTION 13.5 g. of ground steroid I and 4.5 g. of steroid II (R=CH CO) are mixed by mechanical agitation with 300.0 g. of Cremophor EL at 70 C. ina'n atmosphereiof nitrogen. Heating and agitation are continued untilthe steroids have completely dissolved. The mixture is d'iluted with sterile distilled water containing 3.75 g. of'sodium chloride to give a final volume of 1500 ml. and containing 200 mg./ml. of Cremophor EL. Stirring is continued until the solution is homogeneous. i

EXAMPLE 33 AQUEOUS SOLUTION I 0.045 g. of steroid 'I and- 0.015 g. of steroid II (R=CH CO-) are dissolved in 2 ml. of acetone at 20 C. The resultant solution is added to 1 g. of Cremophor EL at 20 C. and stirred until homogeneous. The acetone is removed by a vigorous stream ofnitrogen. The solution is diluted with sterile distilled water containing 0.0125 g. of sodium chloride to give a final volume of 5 ml. and containing 200 mg./ml. of Cremophor EL. Similar solutions were prepared using chloroform or methylene chloride in place of acetone. 1

EXAMPLE 34 AQUEOUS SOLUTION:

0.09 g. of ground steroid I are mixed with 0.03 g. of ground steroid II (R=CH CO) and this added to 2.0 g. of Tween 80. As in Example 33, themixture is mechanically agitated at 70 C. in a stream of nitrogen .untilthe steroids have dissolved. The mixture is diluted with sterile distilled water containing 0.025 g..of sodium, ChlOIldGatO give a final volume of 10 ml. and containing mg./ml. of Tween 80.

EXAMPLE 35 AQUEOUS SOLUTION 0.045 g. of steroid I and 0.015 g. of steroid-1 II (R: (CH CHC0) are formulated as in Example 33. Similar solutions are obtained using steroid II wherein R=C H CO-, HO CCH CH CO or C H CO.

EXAMPLE 36 AQUEOUS SOLUTION 0.045 g. of steroid I and 0.015 of steroid II (R=CH CO) are dissolved in 2 ml. of acetoneat 20 C. The resulting solution is added to 1' & Of Tween 40 at20f C. and stirred until homogeneous. The acetone isremoved by a vigorous stream of nitrogenif The solution" is]diluted with sterile distilled Water containing 0.025 gflof sodium chloride to give a final volume of 1 0 Inland containing mg./ml.ofTween 40. f 3

EXAMPLE 37 AQUEOUS'SOLUTIQN" 0.036 g. of ground Steroid *1 are mixed with'0.0l2 gjof ground steroid II (R=CH CO). This is added to 0.8 g. of

Tween 60. The mixture is mechanically agitated at 70 C. in a stream of nitrogen until the steroids are dissolved. The mixture is diluted with sterile distilled water containing 0.025 g. of sodium chloride to give a final volume of ml. and containing 80 mg./ml. of Tween 60.

EXAMPLE 3:; AQUEOUS SOLUTION 16 mg. of steroid I and 4 mg. of steroid II (R=CH CO) were dissolved in 0.2 ml. of acetone, and 0.2 ml. of Cremophor El wasmixed with this solution. The acetone was removed by passing a stream of nitrogen through the mixture. The resulting solution was mixed with 0.8 ml. of sterile water and containing 200 mg./ml. of Cremophor EL.

EXAMPLE 39 AQUEOUS SOLUTION 0.135 grams steroid I and 0.045 grams of steroid II, (R=CH CO), are dissolved in 2 mls. of acetone at C. The resulting solution is added to 3 grams of Cremophor EL at 20 C.and stirred until homogeneous. The acetone is removed by a vigorous stream of nitrogen. The solution is diluted with sterile distilled water containing 0.025 grams of sodium chloride to give a final volume of 10 mls. and containing 300 mg./ml. of Cremophor EL.

EXAMPLE 40 AQUEOUS SOLUTION 0.045 grams of ground steroid I are mixed with 0.012 grams of ground steroid II (R=CH CO), and the mixture added to 1 gram of Cremophor EL. The mixture is mechanically agitated at 70 C. in a stream of nitrogen until the steroids have dissolved. The mixture is diluted with sterile distilled water containing 0.025 grams of sodium chloride to give a final volume of 10 mls. and containing 100 mg./ml. of Cremophor EL.

EXAMPLE 41 AQUEOUS SUSPENSION 5 ml. of a 20% solution of 3a-hydroxy-5a-pregnane- 11,20-dione in dimethyl formamide at 60 C. were added to 95 ml. of a 2.5% by weight Cremophor EL solution at 5 C. while agitating with a high speed stirrer. The precipitate was washed by centrifugal decantation and a 1% (by weight) suspension prepared in an aqueous medium containing by weight 1% Cremophor El, 5% dextrose, 6% dextran (MW, 40,000) and 100 p.p.m. silicone antiform.

EXAMPLE 42 AQUEOUS SUSPENSION A precipitate of 3a-hydroxy-5a-pregnane-11,20-dione prepared as in Example 1 was formulated as a 1% by weight suspension in an aqueous medium containing by weight 1% Cremophor EL, 0.9% polyvinylpyrrolidone and 100 p.p.m. of silicone antifoam.

EXAMPLE 43 AQUEOUS SUSPENSION 0.2 g. of 3a-hydroxy-5a-pregnane-l1,20-dione finely ground in a fluid-energy mill, and 0.02 g. of Pluronic F68 were made into a thick slurry with distilled water and ball-milled in a small agate mill for 15 minutes and freezedried. The freeze-dried solid may be readily re-dispersed to give a 1% by weight suspension in a solution containing (by weight) 0.2% Pluronic P68, 5% dextrose and 100 p.p.m. of silicone antifoam.

EXAMPLE 44 AQUEOUS SUSPENSION 22 1 500 mg./ml. of a parenterally acceptable non-ionic surface active agent having an HLB value of at least 9.

'2. A composition as claimed in claim 1 wherein the surface active agent has an HLB value of from 9 to 18.

3. A composition as claimed in claim 1 wherein .the surface active agent has an HLB value between 12-15;

4. -A composition as claimed in claim' 1 wherein the surface active agent is selected from the group consisting of a polyoxyethylated castor oil containing at least 35 oxyethylene groups and a polyoxyethylated fatty acid ester containing from 12 to 18 carbon atoms of sorbitan or mannitan. I

5. A composition as claimed in claim 1 wherein the surface active agent is selected from the group consisting of a polyoxyethylated castor oil containing about 40 ethylene oxide units per triglyceride unit, and polyoxyethylene sorbitan monooleate containing about 20 ethylene oxide units.

6. A composition as claimed in claim 1 wherein the surface active agent comprises polyoxyethylene sorbitan monostearate containing about 20 ethylene oxide units or polyoxyethylene sorbitan monopalmitate containing about 20 ethylene oxide units.

7. A composition as claimed in claim 1 which contains above 50 mg./ml. of surface active agent based on the total volume of composition.

8. A composition as claimed in claim 7 which contains above mg./ml. of surface active agent based on the total volume of composition.

9. A composition as claimed in claim 7 which contains not more than 300 mg./ml. of surface active agent based on the total volume of composition.

10. A composition as claimed in claim 7 which contains about 200 mg./ml. of surface active agent, based on the total volume of composition.

11. A composition as claimed in claim 1 which contains at least 2 mg./ ml. of 3u-hydroxy-5a-pregnane-11,20-dione.

12. A composition as claimed in claim 1 which contains at least 4 mg./ml. of 3a-hydroxy 5a-pregnane-1l,20- dione.

13. An anaesthetic composition suitable for use by parenteral administration comprising 300 hydroxy-Sapregnane-1l,20-dione as active ingredient having an average particle size of less than 5 ,um. in suspension in an aqueous suspension medium containing at least 0.5% by weight of a parenterally acceptable surface active agent.

14. A composition as claimed in claim 13 wherein the surface active agent is present in an amount of 0.5-5% by weight.

15. A composition as claimed in claim 14 wherein the surface active agent has an HLB value of at least 9.

16. A composition as claimed in claim 15 wherein the surface active agent has an HLB value within the range of from 9-15.

17. A composition as claimed in claim 14 wherein the surface active agent is a polyoxyethylated derivative of a fatty glyceride oil, having 12-20 carbon atoms, and containing at least 35 oxyethylene groups per mole of fatty oil; a polyoxyethylene ether of an alcohol having 12-18 carbon atoms and containing 10-30 oxyethylene groups; a polyoxyethylene-polyoxypropylene ether containing 5-1-60 oxyethylene groups and 15-50 oxypropylene groups; a polyoxyethylated fatty acid (having 12-18 carbon atoms) ester of sorbitan or mannitan containing 15-30 oxyethylene groups; a polyethylene glycol ester of fatty acid having 12-18 carbon atoms, and containing 6-40 oxyethylene groups; or a phospholipid.

18. A composition as claimed in claim 14 which also contains a parenterally acceptable suspending agent.

19. A composition as claimed in claim 18 wherein the suspending agent is a hydrophilic colloid, polyvinylpyrrolidone, polyvinyl alcohol, sorbital, mannitol, a polyoxyethylene glycol, carboxymethyl-cellulose, colloidal silica or a colloidal silicate.

20. A composition as claimed in claim 18 wherein the suspending agent is a dextran having an average molecular Weight of 15,000 to 70,000.

21. A composition as claimed in claim 18 wherein the suspending agent is present in an amount of from 0.1- 10% by weight of the composition.

22. A composition as claimed in claim 14 also containing an antifoam agent.

23. A composition as claimed in claim 22 wherein the antifoam agent is present in an amount of 50 to 150 p.p.m.

24. A composition as claimed in claim 13 which is isotonic with blood.

25. A composition as claimed in claim 13 wherein the active ingredient is present in an amount of 0.1 to 2.0% by weight of the composition.

26. A composition in the form of a wettable powder, for dispersion in sterile water to provide a composition as claimed in claim 14, said wettable powder comprising 3a-hydroXy-5a-pregnane-l1,20-dione having an average particle size of less than ,um. and a parenterally acceptable surface active agent.

27. A composition as claimed in claim 26 comprising a freeze-dried mixture of 3a-hydroxy-5a-pregnane-l1,20- dione and the surface active agent.

28. A method of inducing anaesthesia in an individual, man or animal, to be anaesthetised, comprising parenterally administering to the individual an eifective amount of a suspension as defined in claim 13.

29. A parenterally injectable anaesthetic composition in dosageunit form for inducing anaesthesia in man, each such unit containing from mg.-300 mg. as a clinically eflective anaesthesia-inducing amount of 3ot-hydroxy- 5u-pregnane-11,20-dione in a sterile pyrogen-free parenterally acceptable liquid vehicle therefor.

30. A composition as claimed in claim 29 wherein at least 1 mg./ml. of 3u-hydroxy-5a-pregnane-11,20-dione is References Cited UNITED STATES PATENTS 3,714,352 l/l973 Davis et al. 424-243 3,337,400 8/1967 Smith 424-240 3,180,797 4/1965 Cachillo et a1. 424-240 X 2,880,138 2/1959 Johnson 424--240 X FOREIGN PATENTS 6,555 2/1969 France. 834,913 5/1960 Great Britain. 941,694 12/ 1963 Great Britain.

OTHER REFERENCES Atkinson et al.: J. Med. Chem. 8: 426-432 (1965), Action of Some Steroids on the Central Nervous System of the Mouse II. Pharmacology.

Kappas et al.: Ama Arch. Intern. Med. 701-708, May 1960 Fever Producing Steroids of Endogenous Origin in Man.

SHEP K. ROSE, Primary Examiner U.S. Cl. X.R. 424-239 

